Pre­scrip­tion safe­guards fail­ing chil­dren

Alarms are ring­ing over the lack of safety data for drugs pre­scribed for chil­dren. Health ed­i­tor Adam Cress­well re­ports

MOST peo­ple as­sume that drugs used in chil­dren are stud­ied more care­fully for po­ten­tially dan­ger­ous side ef­fects than those avail­able for adults. But they are wrong. Far from be­ing sub­ject to more scru­tiny, the use of pre­scrip­tion drugs in chil­dren re­mains a glar­ing blind spot in health sys­tems across the world.

The un­com­fort­able truth is that, for the vast ma­jor­ity of drugs used in chil­dren, there is very lit­tle proper sci­en­tific data to re­as­sure doc­tors about the drugs’ safety and side ef­fects, how well they work — if at all — or what dosages are best.

With­out this data, many drugs are not of­fi­cially ap­proved for use in chil­dren, and the man­u­fac­tur­ers pub­lish no guide­lines for doc­tors in how they should be used in younger age groups. Doc­tors can still pre­scribe drugs for other groups not cov­ered by the orig­i­nal li­cence, such as chil­dren, a prac­tice known as ‘‘ off-la­bel’’ pre­scrib­ing.

Such use may be ap­pro­pri­ate in some cir­cum­stances, but it leaves chil­dren ex­posed to po­ten­tially in­ef­fec­tive or un­safe medicines. Doc­tors pre­scrib­ing off-la­bel are ef­fec­tively left to in­fer from adult tri­als and their own ex­pe­ri­ence what dosages will work best.

Re­cent data shows that from 2002 to 2004 there were 820 sus­pected se­ri­ous ad­verse drug re­ac­tions re­ported spon­ta­neously to the Euro­pean Agency for the Eval­u­a­tion of Medic­i­nal Prod­ucts — 130 of which were fa­tal, and 361 of which caused pro­longed hos­pi­tal­i­sa­tion.

A sep­a­rate Swedish study of ad­verse drug re­ac­tion re­ports re­lated to chil­dren found 158 cases, of which 42.4 per cent were linked to off-la­bel pre­scrib­ing.

Drugs for be­havioural and psy­chi­atric disor­ders, and newer an­tibi­otics and anal­gesics are all ex­am­ples of drugs that are both fre­quently pre­scribed for chil­dren, and for which there is poor ev­i­dence for their safety and ef­fi­cacy.

Stud­ies sug­gest that up to 92 per cent of hos­pi­talised chil­dren are pre­scribed at least one drug off-la­bel dur­ing their stay, and up to 97 per cent of new­born ba­bies. And with the world’s top health body about to step in, pae­di­a­tri­cians and eth­i­cal ex­perts are now say­ing enough’s enough.

‘‘ A lot of pae­di­a­tri­cians have be­come con­cerned in re­cent years that the data isn’t there to re­as­sure them that th­ese pre­scrib­ing prac­tices are safe,’’ says doc­tor Robert Loblay, chair­man of the ethics re­view com­mit­tee for Syd­ney South-West Area Health Ser­vice.

‘‘ There’s been a grow­ing call . . . for phar­ma­ceu­ti­cal com­pa­nies to do the nec­es­sary stud­ies to as­sure them that th­ese drugs are safe and ef­fec­tive (in chil­dren).

‘‘ The phar­ma­ceu­ti­cal com­pa­nies don’t have a lot of in­cen­tive to do that, un­less it’s a big slice of their mar­ket. It’s a very ex­pen­sive thing to run clin­i­cal tri­als.’’

Loblay warned ex­perts at­tend­ing the na- tional ethics con­fer­ence of the Na­tional Health and Med­i­cal Re­search Coun­cil, held in Melbourne in Oc­to­ber, that doc­tors were ‘‘ tread­ing on very thin ice’’ by con­tin­u­ing to pre­scribe drugs to chil­dren when the clin­i­cal tri­als con­ducted to test the safety of those drugs had not in­cluded chil­dren.

In an­swer to a ques­tion, Loblay told the con­fer­ence that hospi­tal ethics re­view com­mit­tees should be more vig­i­lant for the pos­si­bil­ity that drugs might have a use in pa­tients un­der 18.

In such cases, he said ethics com­mit­tees ought to ask re­searchers seek­ing per­mis­sion to con­duct tri­als if chil­dren were in­cluded in the study pop­u­la­tion — and if not, why not.

‘‘ The an­swer may be ‘ we are (in­clud­ing chil­dren), but not at this hospi­tal’,’’ Loblay told Week­endHealth . ‘‘ That’s fine — but we need to be ask­ing the ques­tion.’’

In Lon­don next week the WHO is ex­pected to launch a list of medicines ap­proved for use in chil­dren, to help guide doc­tors about which medicines are safe and ef­fec­tive in chil­dren.

In the mean­time, ex­perts here are push­ing for reg­u­la­tory bod­ies such as the Ther­a­peu­tic Goods Ad­min­is­tra­tion, NHMRC and drug man­u­fac­tur­ers to ad­dress the prob­lem.

Dr Madlen Gazar­ian, a pae­di­atric clin­i­cal phar­ma­col­o­gist, has been warn­ing of the dan­gers caused by in­ad­e­quate data in pae­di­atric pre­scrib­ing for sev­eral years. The chair­woman of the pae­di­atric port­fo­lio of the ther­a­peu­tics com­mit­tee of the Royal Aus­tralasian Col­lege of Physi­cians, Gazar­ian in 2003 wrote an edi­to­rial for the pro­fes­sional jour­nal Aus­tralian Pre­scriber (2003;26(6):122-3) re­port­ing that ad­verse re­ac­tions were more com­mon when drugs were pre­scribed off-la­bel. While many chil­dren had un­doubt­edly ben­e­fited from drug treat­ment, data on ben­e­fits was poor and it was also true that in a few cases

‘ ‘‘ some chil­dren have died as a re­sult’’ of of­fla­bel pre­scrib­ing.

‘‘ Wide­spread off-la­bel pre­scrib­ing re­ally is a ma­jor is­sue — it’s been around for yonks, but seems now to have grabbed enough peo­ple’s at­ten­tion for some­thing to be done about it,’’ Gazar­ian told Week­end Health .

Loblay says al­though doc­tors cur­rently have lit­tle op­tion but to pre­scribe drugs for chil­dren off-la­bel, the fact that they do so re­moves the in­cen­tive for drug com­pa­nies to do fur­ther stud­ies. The prob­lem is com­pounded by the fact that ad­verse re­ac­tions are less likely to be re­ported when the drug was pre­scribed off- la­bel, so there is not even good data to show which drugs are caus­ing most ad­verse re­ac­tions in kids.

There is also a fi­nan­cial an­gle, in that drugs do not at­tract a sub­sidy un­der the Phar­ma­ceu­ti­cal Ben­e­fits Scheme when pre­scribed out­side the terms of their li­cence, so par­ents also end up out of pocket.

Loblay likens the sit­u­a­tion to a sim­i­lar re­search gap that ex­isted for women as late as the 1990s.

‘‘ Fif­teen to 20 years ago . . . most clin­i­cal tri­als did not in­clude women of child­bear­ing age, be­cause they were wor­ried women might be preg­nant (with­out re­al­is­ing it) and the drug might af­fect the de­vel­op­ing baby,’’ Loblay says. ‘‘ So it was stan­dard prac­tice to ex­clude women from most clin­i­cal tri­als. But then peo­ple started to re­alise that we are pre­scrib­ing th­ese drugs for women, but there’s no data to say it’s safe. The (US) Food and Drug Ad­min­is­tra­tion was the first reg­u­la­tory body to say, and the TGA fol­lowed, that to get a drug reg­is­tered com­pa­nies had to in­clude women as well as men. So they all started do­ing it; now it’s stan­dard to do preg­nancy tests on women of child­bear­ing age (when they are en­rolled in tri­als).’’

Loblay, Gazar­ian and oth­ers agree that what’s needed to tackle the ev­i­dence gap for chil­dren is bet­ter re­search — ei­ther by giv­ing bod­ies such as the TGA the power to or­der drug com­pa­nies to in­clude chil­dren in tri­als, or to al­lo­cate pub­lic funds to run tri­als di­rectly — as in the US and Euro­pean Union.

Loblay con­cedes that in­clud­ing chil­dren in tri­als is not as straight­for­ward as in­clud­ing women, due to ethics and safety is­sues. But Gazar­ian says sug­ges­tions th­ese are a ma­jor hur­dle are overblown, and points to the alacrity with which drug gi­ants in the US rushed to take up fi­nan­cial in­cen­tives of­fered by the FDA to run chil­dren-spe­cific tri­als.

‘‘ When­ever you re­move a fi­nan­cial bar­rier or cre­ate a fi­nan­cial in­cen­tive (for drug com­pa­nies), lo and be­hold, the re­search seems able to be done,’’ she says.

‘‘ But it’s tended to hap­pen with more prof­itable drugs with a larger mar­ket. It’s be­com­ing clear that the (US) in­cen­tives are not go­ing to en­sure that all the needed re­search will be done.’’

Ear­lier this year Gazar­ian wrote a dis­cus­sion pa­per for the World Health Or­gan­i­sa­tion on the ques­tion of off-la­bel pre­scrib­ing in chil­dren. While her pa­per said the prac­tice not il­le­gal, ‘‘ and may some­times be ap­pro­pri­ate’’, it was ‘‘ as­so­ci­ated with im­por­tant clin­i­cal and eth­i­cal con­cerns’’.

The pa­per added that off-la­bel pre­scrib­ing ‘‘ does by­pass the safe­guards of the drug reg­u­la­tory process and places a greater onus of re­spon­si­bil­ity on the in­di­vid­ual pre­scriber to as­sess the ben­e­fits and risks of such use for an in­di­vid­ual pa­tient.